SLIT2
protein-codingslit guidance ligand 2, the group of MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the slit family of secreted glycoproteins, which are ligands for the Robo family of immunoglobulin receptors. Slit proteins play highly conserved roles in axon guidance and neuronal migration and may also have functions during other cell migration processes including leukocyte migration. Members of the slit family are characterized by an N-terminal signal peptide, four leucine-rich repeats, nine epidermal growth factor repeats, and a C-terminal cysteine knot. Proteolytic processing of this protein gives rise to an N-terminal fragment that contains the four leucine-rich repeats and five epidermal growth factor repeats and a C-terminal fragment that contains four epidermal growth factor repeats and the cysteine knot. Both full length and cleaved proteins are secreted extracellularly and can function in axon repulsion as well as other specific processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]
- SLIL3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~368.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019719
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0100038
Submitter: LiferaOmics
Genetic evidence – Published (AR scope) No scorable published cases of biallelic (autosomal recessive) SLIT2 variants causing a defined multiple congenital malformation syndrome were identified in the literature. Published genetic evidence total = 0/12 Published (AD context; not scored for AR) PMID: 26026792 – Reports heterozygous SLIT2 variants identified in individuals with CAKUT. Functional assays demonstrated impaired SLIT2 activity, and the authors concluded that SLIT2 variants may confer risk for urinary tract malformations. Because this represents a monoallelic risk/dominant context, it is not scorable under the autosomal recessive model. PMID: 19350278 – Screening study of SLIT2 in familial vesicoureteral reflux identified heterozygous variants; no biallelic AR mechanism was established. PMID: 30476936 – Population-level burden analysis of kidney/genitourinary genes; does not report biallelic SLIT2 cases establishing an autosomal recessive congenital syndrome. AD-context evidence total (not scored for AR) = 0 Genetic evidence – Our case Family 1 – Two affected siblings. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation (affected sibling; both genotyped and phenotype-consistent; conservative assignment) = 0.5; Case-control = 0 Family 1 total = 1.5 Total genetic evidence (published AR + our case) 1.5 / 12 Experimental evidence – Published (conservative and phenotype-aligned) PMID: 15130495 – Slit2–Robo2 signaling is critical for ureteric bud development and kidney morphogenesis in mouse models. Disruption results in urinary tract malformations, supporting a role for SLIT2 in CAKUT biology. These data support kidney/urinary tract developmental roles more strongly than a generalized congenital malformation syndrome. Gene function / biological plausibility (conservative, limited relevance to CNS phenotype described) = 0.5 Experimental evidence total = 0.5 / 6 Overall score Genetic evidence = 1.5 Experimental evidence = 0.5 Overall score = 2.0 / 18
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLIT2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004787.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 84 | 13 | 101 | ||
| missense | 2 | 253 | 12 | 267 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 8 | 8 | ||||
| Total | 2 | 0 | 267 | 96 | 13 | 378 |
Highest pathogenic variant AF is 0.0000035242688
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004778.1 | 37 | MANE Select | |
| Ensembl | ENSP00000422591.1 | 37 | MANE Select | |
| RefSeq | NP_001276064.1 | 37 | Standard | |
| RefSeq | NP_001276065.1 | 36 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slit2 | Danio rerio | Structure: supraoptic tract Quality: process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Axon guidance - Homo sapiens (human)
- Angiogenesis overview
- Spinal Cord Injury
- Olfactory bulb development and olfactory learning
- Robo4 and VEGF Signaling Pathways Crosstalk
Biological Process
- ureteric bud development
- negative regulation of protein phosphorylation
- cell migration involved in sprouting angiogenesis
- negative regulation of leukocyte chemotaxis
- aortic valve morphogenesis
Molecular Function
- GTPase inhibitor activity
- calcium ion binding
- protein binding
- heparin binding
- identical protein binding
Cellular Component
- extracellular region
- extracellular space
- cytoplasm
- plasma membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000504154
- Coding exons
- 37
- Length
- 367302
- Individuals with no LoFs
- 125729
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 19
- Defined
- 125748
- p
- 0.0000756
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.10 | 687 | 860 | 0.799 | 0.0000476 | 10078 |
| Missense (PolyPhen) | 334 | 453.38 | 0.7367 | 5335 | ||
| Synonymous | -0.291 | 325 | 318 | 1.02 | 0.0000179 | 2815 |
| Loss of Function | 7.68 | 7 | 82.1 | 0.0852 | 0.00000425 | 1026 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.000068 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00012 | 0.00012 | rare |
| South Asian | 0.000038 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions. SLIT1 and SLIT2 seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb. In spinal chord development may play a role in guiding commissural axons once they reached the floor plate by modulating the response to netrin. In vitro, silences the attractive effect of NTN1 but not its growth- stimulatory effect and silencing requires the formation of a ROBO1-DCC complex. May be implicated in spinal chord midline post- crossing axon repulsion. In vitro, only commissural axons that crossed the midline responded to SLIT2. In the developing visual system appears to function as repellent for retinal ganglion axons by providing a repulsion that directs these axons along their appropriate paths prior to, and after passage through, the optic chiasm. In vitro, collapses and repels retinal ganglion cell growth cones. Seems to play a role in branching and arborization of CNS sensory axons, and in neuronal cell migration. In vitro, Slit homolog 2 protein N-product, but not Slit homolog 2 protein C-product, repels olfactory bulb (OB) but not dorsal root ganglia (DRG) axons, induces OB growth cones collapse and induces branching of DRG axons. Seems to be involved in regulating leukocyte migration. {ECO:0000269|PubMed:10102268, ECO:0000269|PubMed:10864954, ECO:0000269|PubMed:10975526, ECO:0000269|PubMed:11239147, ECO:0000269|PubMed:11309622, ECO:0000269|PubMed:11404413}.;
Recessive Scores
- pRec
- 0.218
Intolerance Scores
- RVIS EVS
- -2.18
- RVIS percentile EVS
- 1.4
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.744
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |